Genetic Influences on Alcoholism Risk

Researchers have used two different strategies to determine the relative contributions of genes and shared environment to the development of alcoholism among family members: the adoption study and the twin study. Adoption studies compare the risk to biological relatives with the risk to adoptive relatives of alcoholics. Twin studies compare identical and fraternal pairs of twins reared in the same environment. Evidence indicates an important genetic influence on alcoholism risk; this influence appears as strong in women as in men. These results have been remarkably consistent despite major differences between research methods.

T he tendency for alcoholism to run article briefly summarizes and updates a ADOPTION STUDY FINDINGS in families has long been recog recent review reanalyzing the major pub nized through controlled family lished studies on gender differences in the studies beginning in the 1950's (Amark genetic contribution to alcoholism risk A Pioneering Study 1951;Bleuler 1955;Cotton 1979). Re (Heath et al. in press). (For more informa The first adoptionstudy evidence for an search findings have indicated that alco tion on the methodology of these types of important genetic contribution to alco holism can arise in families through genetic research, see the related articles in the Tools holism risk was produced in Scandinavia. or environmental causes or through a mix of Genetic Research section, In Copenhagen, Denmark, Goodwin and ture of both. Researchers have used two This article focuses on studies that colleagues (1973, 1974, 1977a,b) used different strategies for determining the have systematically used samples ascer official registries to identify biological proportional contributions of genes and tained from birth or adoption records. parents who had histories of alcoholism shared family environment to the develop Unfortunately, however, this review ex and who had given up a child for early ment of alcoholism among family members: cludes several important studies (Gurling adoption by nonrelatives. The researchers the adoption study and the twin study. Pickens et al. 1991;Caldwell used biological parents who had no known adoption study compares the risk of alco and Gottesman 1991; McGue et al. 1992; histories of alcoholism but who also had holism in biological relatives with the risk Heath et al. 1994), because various techni given up a child for early adoption as con in adoptive relatives of alcoholics (e.g., an cal issues place those studies beyond the trol subjects. Interviews were conducted adoptedaway child of an alcoholic par scope of this review (for further details, with adult sons and daughters of both ent). In contrast, the twin study compares see Heath et al. in press). groups to determine the prevalence of the risk of alcoholism in identical and alcoholism among them. The researchers fraternal pairs of twins reared in the same speculated that if the genetic contribution ANDREW C. HEATH, D.PHIL., is an associate environment. Although studies of the to alcoholism were important, the rates of professor in the Department of Psychiatry, genetic aspects of alcoholism have ex alcoholism should be higher in the adopted Washington University School of Medicine, panded to include molecular and animal St. Louis, Missouri. away offspring of the alcoholic biological studies, it is helpful to reexamine adoption parents than in the adoptedaway offspring and twin evidence; both types of data are This work was supported by National Insti of the control parents. important bases for subsequent research on tutes of Health grants AA07535, AA07728, The investigators also identified a subset genetic influences on alcoholism. This AA09022, AA10339, and AA10249. of biological parents who had given up one child for adoption but had reared a second child themselves. This subset could demon strate the effects of environment on the children. If growing up in the environment of an alcoholic parent contributes signifi cantly to alcoholism risk, this risk should be higher in the nonadopted sons and daughters of alcoholics, compared with the adoptedaway sons and daughters. According to the findings, 8.9 percent of the fathers and 1.6 percent of the moth ers who gave their offspring up for adop tion had been hospitalized for alcoholism. Heath and colleagues (in press) estimated that the proportion of all adults in the pop ulation of Copenhagen who were in the same age range as the biological parents and who had been hospitalized for alco holism at some stage in their lives was 2 percent for men and 0.5 percent for wom en. These figures are almost certainly over estimates. Compared with what would be expected for the population as a whole, the lifetime prevalence of hospitalization for alcoholism is at least four times higher in the biological fathers and three times higher in the biological mothers of the children who were given up for adoption. There fore, if alcoholism is genetically influ enced, then adoptees as a group would be at higher risk than the general population and would have elevated rates of alco holism. The higher genetic risk among adoptees is a recurrent finding in the major adoption studies and should be taken into consideration when analyzing results. colleagues (1973, 1977a,b) reported an estimated risk ratio of 3.6 for adoptedaway sons of alcoholics and 3.4 for nonadopted sons of alcoholics, com pared with an assigned risk value of 1.0 for control adoptees. 1 Likewise, only 2 percent of adoptedaway daughters of alcoholics and 3 percent of nonadopted daughters were diagnosed as having histories of alcoholism, compared with 4 percent of control adoptees, giving risk ratios of only 0.5 and 0.75. Risk ratios using estimates of lifetime alcoholism prevalence in the gener al population are unchanged in men but become 2.0 and 3.0 for adopted and non adopted daughters of alcoholics based on Goodwin's estimated 1percent prevalence for alcoholism in women. According to these findings, rates of alcoholism are significantly elevated in both the adopted 1 A risk ratio is a measure of association between two variables. Here, the control adoptees have been as signed a risk of 1 because they are the group against which the other groups in the study are measured. A risk ratio of 3.6 for adoptedaway sons of alcoholics thus means that that group is 3.6 times as likely as the control adoptees to become alcoholic. and nonadopted sons of alcoholics, results which are consistent with a genetic influ ence on alcoholism risk in men. Results for women are not significant.
What can we conclude from these findings? First, it appears that there is a genetic influence on alcoholism in men. The Copenhagen data do not support a firm conclusion with respect to a genetic influence in women. These data also do not provide evidence for a significant environ mental impact of parental alcoholism, be cause the risk to nonadopted offspring is no greater than the risk to adopted off spring, although moderately strong envi ronmental influences could remain undetected given the sample sizes used.
A limitation of the Copenhagen study is that no direct interviews were conducted with adoptive parents; therefore, the possi bility that selective placement occurred, leading to an aboveaverage probability that the child of an alcoholic biological parent would be raised by an alcoholic adoptive parent, cannot be completely ruled out. Such selective placement would cause the importance of genetic effects to be overestimated. It seems implausible, however, that this effect could completely explain the elevated risk to adoptedaway sons of alcoholic parents, since their risk is no less than that to nonadopted sons of alcoholics. Family history reports by the adoptees suggest that, if anything, alcohol problems were less prevalent in the adop tive fathers of the adoptees who were sons of alcoholics (12 percent) than in the con trol adoptees (22 percent), a result which also suggests that selective placement of adoptees could not explain these findings.

More Recent Adoption Studies
Sweden. A separate adoption study con ducted in Scandinavia Cloninger et al. 1981Cloninger et al. , 1985 repli cated the Copenhagen study findings using different procedures. No direct interviews with adoptees were conducted. Prevalence of alcoholism was estimated from records of the Stockholm Temperance Board. Re cords were obtained for both biological parents and their adoptedaway offspring. Although additional information was available from other agencies (e.g., wel fare reports and national health insurance records) and was used in some articles by Cloninger and colleagues, the data reana lyzed here are limited to Temperance Board registration data as reported by Cloninger and colleagues (1985).
By using archival records, the Stockholm study was able to obtain data on the entire sample of adoptees. Thus, pre valence rates for alcoholism are available for the total sample of biological parents and adoptees. Significant associations are found between Temperance Board regis trations for biological fathers and their adoptedaway sons (i.e., a risk ratio of 1.3) and for biological mothers and their adoptedaway daughters (i.e., a risk ratio of 2.9). These ratios are consistent with a genetic contribution to alcoholism risk. However, the risk ratios for oppositesex pair comparisons (i.e., motherson and fatherdaughter pairs), although greater than one, are not statistically significant. Cloninger and colleagues (1985) re ported no significant association between adoptee alcoholism and Temperance Board registration in the adoptive parents. How ever, one cannot conclude from this find ing that rearing environment in general has little impact on alcoholism risk. In less than 5 percent of adoptive families did either parent have a Temperance Board registration, implying that adoptees were being placed in lowrisk environments. United States. The only recent United States adoption studies on alcoholism for which results have been published are those conducted by Cadoret in Iowa. The fact that only one investigator has been able to conduct such studies may reflect the high degree of tenacity required to overcome State privacy regulations restricting access to information about the biological families of adoptees. In his earliest studies, Cadoret studied samples from Lutheran Social Services (LSS) (Cadoret et al. 1985;Cadoret 1994) and Iowa Children and Family Services (CFS) (Cadoret 1994;Cadoret et al. 1987). More recently, he has also studied samples recruited from a series of Catholic Adoption Agencies (CAA) (Cadoret 1994;Cadoret et al. 1995;Cutrona et al. 1994) and from four other adoption agencies (Cadoret 1994).
Original publications on the LSS and CFS samples are not always easy to inter pret, as three types of control populations were used: adoptees with antisocial behav ior in biological family members (usually, but not exclusively, parents), 2 adoptees with alcohol problems in biological family mem bers, and control adoptees. Results were reported for alcoholic versus nonalcoholic and for antisocial versus nonantisocial bio logical backgrounds. A subsequent publica tion (Cadoret 1994) has reported numbers for the alcoholic biological background versus control comparisons for males, and those numbers are used here; however, no similar breakdown appears to have been published for female adoptees. Thus, the "control" sample of female adoptees for each study includes adoptees from a nonal coholic but antisocial biological background. Insofar as an overlap exists between genetic risk factors for alcoholism and antisocial behavior, this overlap will cause the risk ratios for women to be underestimated.
The two earliest Iowa adoption studies (i.e., the LSS and CFS) show significantly elevated risk to adoptedaway sons from alcoholic biological backgrounds compared with control adoptees (i.e., risk ratios of 3.5 and 3.6, respectively), consistent with a genetic influence on alcoholism risk in men. For male adoptees in the remaining two samples, the risk to those from an alcoholic background is not significantly higher than that for control adoptees. In these latter studies, however, the rates of alcoholism are high, even in the control adoptees (from 55 to 58 percent), raising the possibility that the entire sample of adoptees, on average, came from highrisk biological backgrounds. Postulating a 28 percent prevalence rate for alcohol prob lems in the general population, the risk of alcoholism in adoptedaway sons from al coholic backgrounds is significantly greater than that for the general population.
Data from the LSS and CFS studies also allow us to examine the association between alcohol problems in the adoptive family and the occurrence of alcoholism in the adoptee. In each case, a significantly elevated alco holism risk was found for male adoptees (i.e., risk ratios of 2.7 in the LSS study and 2.1 in the CFS study) raised in adoptive families in which at least one member experienced alcohol problems, compared with male adoptees raised in adoptive families in which no one else experienced alcohol problems. It should be noted, how ever, that because alcohol problems in the adoptive families could include problems experienced by siblings, analysis could overestimate the influence of the adoptive parents on the adoptees' outcomes.
For female adoptees, data are available from both the LSS and CAA studies. Al coholism in the biological background was associated with an increased risk of alcoholism in the LSS study but with a reduced risk in the CAA study. However, a high rate of alcoholism in female control adoptees in the latter study (28 percent) suggests that a similar problem exists to that observed for males from this source, with a population of adoptees that is at high risk for developing alcoholism. Com pared with an estimated prevalence of 10 percent for female alcoholism, the rate of alcoholism in adoptedaway daughters of alcoholics still is significantly elevated.

TWIN STUDIES
Twin studies of alcoholism have examined the increased risk of developing alcoholism in identical (i.e., monozygotic, or MZ) twins of alcoholics (who share the same genetic makeup as their alcoholic twins) and in fraternal (i.e., dizygotic, or DZ) twins of alcoholics (who, on average, share only half their genes) compared with the general population. If genetic influences or envi ronmental factors shared by twin pairs growing up together are important, the percentage of twins of alcoholics with a current or past history of alcoholism should be much higher than the percentage in the general population. If genetic influ ences, in particular, are important, a signif icantly higher risk ratio should occur in MZ compared with DZ twin pairs.

The Initial Study
The first twin study of alcoholism was conducted in Sweden in the 1950's by Kaij (1960). This study used birth records and Temperance Board registration data to identify alcoholic male twins from Skåne, Sweden. Kaij conducted followup inter views with alcoholic twins and their co twins, 3 showing that twins having at least one Temperance Board registration exhib ited a fivefold increase in probability of being diagnosed as alcoholic, thereby con firming the validity of registrations as a measure of alcohol problems. He also noted, however, that those twins with social prob lems were likely to be overrepresented among Temperance Board registrants.
Using as a criterion the requirement of at least one Temperance Board registration, the proportion of registered twins whose cotwins were also registered was signifi cantly higher for the MZ than for the DZ pairs. Approximately 61 percent of MZ co twins of twins with an alcohol problem and a significantly lower fraction (39 percent) of DZ cotwins of twins with an alcohol problem were registered. Based on national data, Kaij (1960) reported a lifetime alco holism prevalence of 7.7 percent for males in the general population. Using this value gives a risk ratio of 9.1 for male MZ twins of registered cotwins and 6.2 for DZ co twins. Again, these data are consistent with a genetic influence on alcoholism risk. 3 A cotwin is one member of a pair of twins.

Other Twin Studies
Subsequent studies using samples ascer tained from birth records have confirmed, without exception, a higher risk to MZ compared with DZ twins of alcoholics, although this difference has not always been significant. Hrubec and Omenn (1981) identified alcoholism cases in a followup of a series of male samesex twin pairs born between 1917 and 1927, identified originally from birth records, in which both twins engaged in military service during World War II. The re searchers reviewed Veterans Ad ministration (VA) medical records of approximately 13,486 male twin pairs, all of whom were age 50 at the time of the record review, to identify cases of alco holism or alcoholic psychosis. Only 2.6 percent of MZ twins and 3.1 percent of DZ twins were reported as having any treatment history for alcohol problems. If one twin had a history of alcohol prob lems recorded, however, the probability that his or her twin also did was 26.3 percent for MZ twins (i.e., a risk ratio of 10.0) and 11.9 percent for DZ twins (i.e., a risk ratio of 3.8). These riskratio differ ences were highly statistically significant.
Three studies in Scandinavia have matched twin registries to national data bases containing hospital discharge data. In Finland, Koskenvuo and colleagues (1984) conducted such a match using only an alcoholism discharge code and found a significantly higher risk ratio for male MZ than for male DZ twins of males hospital ized for alcoholism (i.e., 11.8 versus 5.5). Romanov and colleagues (1991) conducted a further followup of a subsample of the same twin cohort using a broader definition of alcoholism that included alcohol abuse related discharge codes (e.g., alcoholic liver cirrhosis and alcoholic psychosis) and found a nonsignificant trend in the same direction (i.e., risk ratios of 8.8 versus 4.6, respec tively). In Sweden, col leagues (1991, 1992) performed a similar match of the Swedish twin registry to alcoholrelated discharge codes; these data again showed an elevated risk ratio in MZ, compared with DZ, male twins (i.e., 7.9 versus 5.3), although again the difference was not significant. For women, Koskenvuo and colleagues (1984) found no samesex twin pairs in which both twins had an alco holism discharge code, making it impossible to estimate a risk ratio. col leagues (1991, 1992) found substantial risk ratios for MZ and DZ female twins of female alcoholics (i.e., 41.9 and 16.5, respectively), but again these do not differ significantly.
The only other study to use a sample of twin pairs identified from birth records (Kendler et al. 1992) included only female samesex pairs. 4 Alcoholism was assessed using standard diagnostic criteria as de fined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) (American Psy chiatric Association 1987). The relatively high lifetime prevalence rates of alcohol dependence (i.e., 10.2 percent for DZ twins and 8.1 percent for MZ twins) are consistent with what has been reported for a national probability sample in the National Co morbidity Survey (Kessler et al. 1994). 5 As in any survey of a general community sample, the majority of cases may be ex pected to be mild (for example, see Heath et al. 1994). Once again, however, rates of alcoholism were significantly elevated in both MZ and DZ twins of alcoholics (i.e., risk ratios of 3.9 and 2.4, respectively), and evidence showed a higher risk to MZ than to DZ twins (although this result did not reach statistical significance). 6

COMBINING RESULTS FROM DIFFERENT STUDIES
How can results across different studies or even within studies (e.g., between men and women) be compared? Riskratio estimates cannot simply be pooled because of differ ences in the estimated rates of alcoholism. Estimates of the prevalence of alcoholism are highly variable, depending on how alcoholism is defined. Thus, Kendler and colleagues (1992) reported a lifetime pre valence of alcohol dependence defined by DSM-III-R of 8 to 10 percent in women, whereas Hrubec and Omenn (1981) reported a prevalence in men of alcoholism treated through the VA system of only 2.6 to 3.1 percent. Estimates of risk ratios for relatives of alcoholics, which express risk to rela tives as a ratio of the risk in the general population, are similarly variable.
One approach for comparing studies of disorders having a complex mode of inher itance has been a liability, or "threshold," model. In this model, a person's liability to develop alcoholism is assumed to be deter mined by the combined effects of many 4 An extension of that study, which includes male same sex pairs as well as oppositesex pairs, is now in progress. 5 This survey was designed to study the cooccurrence of alcohol and other drug use disorders with psychiatric disorders in the United States. 6 However, results reached significance if the diagnostic criteria were either narrowed (to require withdrawal symptoms) or broadened (to include problem drinking). separate risk factors-genetic, environ mental, or both. The distribution of liabil ity to alcoholism in the general population is assumed to be continuous and to follow a bell curve. The majority of people ex hibit an intermediate risk; some, a very low risk; and some, a very high risk. The model assumes that those whose liability exceeds some critical value (i.e., thresh old) will become alcoholic. Changing the definition of alcoholism merely shifts the threshold to the right (i.e., fewer but more severe cases) or to the left (i.e., more but less severe cases). (For further discussion of the liability model in twin studies, see side bar by Prescott and Kendler,. The liability model provides a natural framework for combining data from differ ent studies using widely different defini tions of alcoholism. It also allows us to compare the importance of genetic and/or shared environmental influences on alco holism risk in men and women, despite the significant gender differences in the preva lence of alcoholism. In genetic studies, these liability correlations are usually expressed in terms of the causes of varia tion in alcoholism liability. Here, a simpli fied model is used that allows for the contributions of genes, family environ ment, and nonshared environmental expe riences and ignores such complications as geneenvironment correlation (i.e., the tendency of people at high genetic risk to be exposed also to highrisk environments) and, for adoption data, selective placement. Nonetheless, this simplified model pro vides a good starting point for comparing results from different studies.

Genetic Influences on Alcoholism Risk
For individual studies, Heath and colleagues (in press) estimated the proportions of vari ability in alcoholism liability explained by genetic and family environmental influ ences. Several results are striking.
First, our analysis does not support the common belief that genetic influences on alcoholism risk may be more important in men than in women.
Second, two studies appear to be out liers, producing results at variance with the general trend. The estimate of the shared environmental contribution to alcoholism risk from the Kaij (1960) study is much greater than in all other studies. The rea sons for this are unknown, although it is possible that in the work by Kaij some registrations were accidentally overlooked. However, once one twin from a pair was identified with a registration, the records were searched more thoroughly to deter mine whether the cotwin also had been registered. Cadoret's study of four adoption agencies (Cadoret 1994;Cadoret et al. 1995) has yielded a high estimate of the genetic contribution to variability in alcoholism risk, which does not differ significantly from a probability of 100 percent (i.e., complete heritability). Further inquiry is needed to determine the cause of this result.
Third, the combined genetic variability and family environmental contributions to alcoholism risk in the Iowa CFS and LSS studies total 100 percent, implying that nonshared environmental effects have no impact on alcoholism risk. This result seems implausible. As noted previously, alcoholism in adoptive families could include drinking problems that were caused by the behavior of the adoptee. Thus, the contributions of environmental and genetic variability would not be independent of each other. With the ex ception of the two outlier studies, in the remaining studies, nonshared environ mental influences account for at least 30 percent of the variation in alcoholism risk.
In a metaanalysis, we have jointly analyzed data from all studies already mentioned, except the two outliers. Meta analysis is used to combine data from many different studies to improve the ability to detect small effects by improving the preciseness of estimates. Estimates of genetic and environmental effects did not appear to vary significantly within the group of U.S. studies or the group of Scandinavian studies. In analyzing the U.S. data, estimates for the contributions of the family environment obtained from the adoption data (i.e., based on the Cadoret LSS and CFS samples) and from the twin data were considered separately because of concerns about the measure of the adoptive family's environmental contribution to alcoholism mentioned previously.
Within both the U.S. and Scandinavian studies, no significant gender differences were found in the genetic contribution to alcoholism risk. In the Scandinavian data, genetic factors appear to be more impor tant in women than in men (a pattern that is seen in both the Swedish adoption and Swedish twin studies), but no statistically significant difference exists. Based on the U.S. data, genetic effects account for approximately 60 percent of the variance in alcoholism risk in both men and wom en, and the twin data suggest that there is no significant effect of family environ ment. The U.S. adoption data suggest that the adoptees' family environments may account for onethird of the variance. The Scandinavian data yield a lower estimate for the importance of genetic influences (i.e., 39 percent) and a modest but signifi cant estimate for family environmental influences (i.e., 15 percent). This differ ence between the U.S. and Scandinavian data appears to be explained largely by differences in Scandinavian males, with estimates for Scandinavian women being close to those for U.S. men and women.

CONCLUSIONS
The reanalysis reviewed here has confirmed the consistency of the evidence for an im portant genetic influence on alcoholism risk from both twin and adoption studies. The genetic influence on alcoholism in women appears as strong as that in men. Many studies that followed children of alcoholics prospectively to identify precursors of alcoholism risk have focused on sons of alcoholics, assuming a stronger genetic influence in men than in women (for fur ther discussion of markers, see the article by Anthenelli and Tabakoff, pp. 176-181). This assumption does not appear to be supported by the data, at least for the definitions of alcoholism analyzed here.
Second, estimates from Heath and colleagues (in press) have been remarkably consistent across groups born in different time periods-that is, whether one com pares U.S. male twins born in the 1920's who served in World War II or U.S. adoptees born in the 1940's, 1950's, and 1960's, or whether one compares Swedish female adoptees born from 1930 to 1949 and Swedish female twins born as late as 1967. Given the changes that occur over time in the levels of alcohol consumption and the rates of alcohol problems, it is somewhat surprising that the importance of genetic factors has not changed, although a similar finding has been observed for ge netic influences on smoking behavior (Heath et al. 1993;Heath and Madden 1995). It could have been anticipated that increasing exposure to alcohol would make genetic factors become more important.
Third, results have been remarkably con sistent despite major differences between samples in the methods used to diagnose alcohol problems, ranging from hospitaliza tion or other treatment records and Swedish Temperance Board registrations to direct interview assessments, which, in community samples, include a relatively high propor tion of "mild" cases. This pattern would only be expected if the same risk factors, genetic or environmental, operate across the entire spectrum of alcohol problems, from mild to severe. Kendler and colleagues (1992) noted this finding in women.
Fourth, an apparent crosscultural dif ference in the importance of genetic influ ences on alcoholism risk is evident from these data, which, if confirmed, would be an important example of geneenvironment interaction. The data raise the possibility that, at least in men, genetic factors may have a reduced impact on alcoholism risk in some environments (e.g., Scandinavian) compared with other environments (e.g., U.S.). However, this could be an artifact of differences in research methodology, as no studies led by the same investigators and using a common research methodology have been conducted in both Scandinavia and the United States.
Some important limitations should be noted. Although studies now include His panic, AfricanAmerican, Asian, and other minority groups, most earlier studies pre dominantly used samples of European ancestry. The generalizability of findings in populations of nonEuropean ancestry remains to be determined.
This article has focused on questions about the relative importance of genetic and environmental influences on alco holism. However, such questions are only a starting point for behavioral genetic research on alcoholism. Understanding more about how genes and environment act, coact, and interact to determine differences in alcoholism risk remains a key goal of ongoing twin and adoption studies. Meanwhile, the evidence from twin and adoption studies has provided researchers with the impetus to investi gate other methods of genetic alcoholism research, such as molecular genetics studies and the development of animal models. Together, these endeavors will continue to shed light on the genetic contribution to alcoholism. ■